PURPOSE:Patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for or not proceeding to autologous stem-cell transplantation (ASCT)-often because of age or frailty-have limited opportunities to receive multiple effective lines of therapy, underscoring the need for novel frontline strategies. METHODS:In this phase II, open-label, single-arm trial (ClinicalTrials.gov identifier: NCT05860036), patients received 3-4 cycles of protocol-allowed induction, followed by B-cell maturation antigen (BCMA) CAR-T infusion, and subsequent consolidation and lenalidomide maintenance. The primary end point was the rate of minimal residual disease (MRD) negativity (10-5) at Month three postinfusion. RESULTS:Between April 4, 2023, and December 26, 2024, 43 patients were screened, 40 were enrolled, and 36 received infusion (median age, 68 years [46-75]). In the infused cohort, the MRD negativity rate at Month three postinfusion was 100% (36 of 36; 95% CI, 90.3 to 100.0). With a median follow-up of 15.8 months postinfusion (range, 4.3-26.0), no MRD recurrence was observed. The complete response rate (CRR) increased from 33.3% (12 of 36; 95% CI, 18.6 to 51.0) preinfusion to 69.4% (25 of 36; 95% CI, 51.9 to 83.7) at Month 3% and 94.4% (34 of 36; 95% CI, 81.3 to 99.3) at last follow-up. The most common grade 3 to 4 adverse events were transient cytopenia, including lymphopenia (100%), neutropenia (88.9%), leukopenia (80.6%), thrombocytopenia (19.4%), and anemia (8.3%). Cytokine release syndrome occurred in 52.8% of patients (all grade 1 to 2), immune effector cell-associated neurotoxicity in 5.6% (all grade 1), and infections in 30.6% (grade ≥3 in 19.4%). No deaths or disease progressions occurred by cutoff. CONCLUSION:Frontline BCMA CAR-T therapy induces deep, rapid, and durable remissions with a manageable safety profile in the NDMM population ineligible for or not proceeding to ASCT. These findings support its investigation as a potentially practice-changing strategy for this population.

Abstract Mantle cell lymphoma (MCL) is a biologically heterogeneous B-cell malignancy. Although genomics and transcriptomics have delineated parts of the MCL disease spectrum, proteomics remains largely unexplored. Here, we conducted a comprehensive proteogenomic analysis integrating genomics, transcriptomics, and proteomics on peripheral blood samples from 27 patients with MCL and 4 healthy donors to investigate the translational and posttranslational dimensions of MCL. Our study identified 1296 downregulated and 468 upregulated proteins in MCL cells. The splicing pathways were significantly upregulated at both the mRNA and protein levels, suggesting a critical role for aberrant RNA splicing in MCL pathogenesis. Integration of proteomic data with genetic aberrations revealed immunoglobulin heavy chain variable mutational status and CCND1 mutation are associated with distinctive transcriptomic and proteomic profiles, which correspond to significant differences in clinical outcomes. A multiomics molecular stratification model incorporating proteomic data showed superior predictive power for patient survival compared with single-omics models (concordance index, 0.83 vs 0.74). This study provides, to our knowledge, the first comprehensive proteogenomic profile of MCL, offering novel insights into its molecular mechanisms and clinical behavior. The identification of molecular subtypes and prognostic protein signatures underscores the potential of proteomics to guide precision medicine strategies for MCL.

To evaluate the prognostic value of TP53 mutations in patients with diffuse large B-cell lymphoma (DLBCL). We retrospectively analyzed the clinical data and gene sequencing results of 253 newly diagnosed DLBCL. Survival and correlation analyses were performed. We further revealed significant prognostic heterogeneity among different TP53 hotspot mutations, with mutations at codons G245, R175, R273, and R282 indicating a poorer prognosis. Within the DBD, mutations in exons 5, 7, and 8 were associated with poorer PFS, while mutations in exons 5, 6, and 8 were linked to poorer OS. Additionally, mutations in the Loop-L2, Loop-L3, and LSH motifs within the DBD were all significantly associated with unfavorable PFS and OS. Notably, in the cohort treated with R-CHOP plus novel agents (R-CHOP + X), there were no significant differences in response rates or survival between TP53-mutated and TP53 wild-type patients, suggesting this combination may overcome the adverse prognosis associated with TP53 mutations.TP53 mutation is a crucial adverse prognostic factor in DLBCL. Given the significant prognostic heterogeneity among different TP53 hotspot mutations, a more refined risk stratification based on the TP53 mutational profile is warranted in clinical practice. For patients with high-risk mutations, combining R-CHOP with targeted therapies and exploring novel combination strategies targeting specific pathways are recommended. In contrast, standard R-CHOP may remain an appropriate option for patients with low-risk mutations. Future prospective trials are needed to validate the efficacy of R-CHOP combined with targeted agents in TP53-mutated DLBCL to optimize treatment strategies and improve patient outcomes. TP53mutations occur in approximately one-third of diffuse large B-cell lymphoma (DLBCL) patients. Missense mutations in the DNA-binding domain are the most common type of TP53alterations. Specific hotspot mutations (R273, R248, R175) are associated with inferior prognosis. TP53 mutation status provides independent prognostic information beyond the International Prognostic Index. Combined analysis of TP53 mutation and protein expression improves risk stratification.

This study evaluated the efficacy and safety of obinutuzumab plus bendamustine (GB) as first-line treatment for indolent B-cell lymphomas. In this prospective, multicenter, single-arm trial (NCT06415708), adults with newly diagnosed indolent B-cell lymphomas—including follicular lymphoma (FL), marginal zone lymphoma (MZL), Waldenström macroglobulinemia (WM), hairy cell leukemia variant (HCL-v), and unclassified B-cell lymphoproliferative disorder (BCLPD-U)—received six induction cycles of GB followed by 2 years of obinutuzumab maintenance in responders (⩾ partial response). The primary endpoint was overall response rate (ORR), whereas secondary endpoints included complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Among 220 enrolled patients (149 with FL and 71 with non-FL), 210 completed ⩾ 3 treatment cycles. At a median follow-up of 13.1 months, ORRs in the different patient subgroups were 96.6

Waldenström macroglobulinemia (WM) is a rare indolent B-cell lymphoma with marked clinical and molecular heterogeneity. Clinical risk models, including IPSSWM, rIPSSWM, and MSSWM, were developed prior to the widespread use of Bruton tyrosine kinase inhibitors (BTKi), and their performance in the BTKi era remains uncertain. In addition, the prognostic impact of various genomic alterations is controversial. We retrospectively analyzed 453 symptomatic WM patients, including 203 who received non-BTKi therapy and 250 who received BTKi-based therapy. All three models significantly stratified prognosis in the non-BTKi cohort, with rIPSSWM showing the highest predictive accuracy, but none effectively predicted survival in BTKi-treated patients. Notably, among patients receiving first-line BTKi-based therapy, high-risk patients by any model achieved survival outcomes comparable to those of lower-risk patients, suggesting that upfront BTKi can overcome the adverse impact of high-risk clinical features. At the molecular level, MYD88 mutation was significantly associated with favorable outcomes exclusively in patients treated with first-line BTKi-based therapy, while CXCR4 and TP53 mutations predicted significantly inferior prognosis in both BTKi-based and non-BTKi cohorts. Our findings indicate that although clinical risk models remain relevant for patients receiving non-BTKi therapy, molecular features, especially MYD88, CXCR4, and TP53 mutations, provide superior prognostic insights for patients with BTKi-based regimens.

Approximately 5%-10% of patients with chronic lymphocytic leukemia (CLL) develop autoimmune hemolytic anemia (AIHA). However, its pathogenesis and prognostic significance remain heterogeneous and incompletely defined. This study investigated the clinical and molecular features of CLL-associated AIHA and aimed to clarify its prognostic impact. We retrospectively analyzed baseline characteristics, first-line treatments, and survival outcomes in 1,404 patients with CLL. The incidence of AIHA was 10.4%, with 69.2% of cases classified as warm-antibody AIHA (wAIHA). CLL patients with AIHA were characterized by male predominance, advanced disease stage, IGHV4-34 usage, and other adverse biological features. Among the tested genes, DNMT3A mutations were more frequent in patients with AIHA, while MYD88 mutations were enriched in cold-antibody AIHA (cAIHA). Although AIHA conferred a significantly adverse prognostic impact on CLL outcomes, this effect was markedly attenuated with targeted therapies. Unmutated IGHV status predicted inferior outcomes in the overall CLL cohort, but not among patients with AIHA. Our findings underscore the importance of routine AIHA screening in high-risk CLL and support consideration of targeted therapies to mitigate the adverse impact of AIHA on long-term survival.

Utilization of novel Bruton tyrosine kinase inhibitors (BTKi) has become common for treating CLL/SLL patients, yet limited evidence exists on the clinical characteristics and outcomes following BTKi therapy discontinuation in China. This multicenter retrospective study analyzed 37 CLL/SLL patients in China who discontinued BTKi therapy. The mean age at discontinuation was 62.67 years, with the majority being male (67.57%). Most patients (62.16%) were relapsed/refractory (R/R) CLL/SLL patients prior to BTKi treatment, and 37.84% were treatment-naïve patients. Treatment-naïve patients were significantly younger than R/R patients (56.93 vs. 66.16 years, p = 0.005). Discontinuation reasons included resistance (48.65%), intolerance (32.43%), and other factors (18.92%). The most frequently used regimen among the post-BTKi first subsequent therapies was the anti-CD20 antibody combination therapy (52.90%). The overall disease control rate during BTKi treatment was 78.13%. The median progression-free survival (PFS) for BTKi therapy was 19.09 months, 19.09 months for treatment-naïve patients, and 14.39 months for R/R patients. The minimum median PFS was observed in patients with resistance (7.86 months). After BTKi discontinuation, median PFS was shorter: 8.87 months for first subsequent therapy and 5.32 months for second subsequent therapy. No significant difference was observed in overall survival. These findings illustrate the impact of prior treatment and discontinuation reasons on subsequent outcomes.

Background: Autoimmune hemolytic anemia (AIHA) complicates 5%-10% of chronic lymphocytic leukemia (CLL) cases, significantly worsening outcomes. While linked to clonal B-cell autoantibodies and immune dysregulation, its precise pathogenesis and prognostic drivers remain incompletely defined, especially in the targeted therapy era and in Asian populations where data are scarce. Methods: We retrospectively analyzed 1404 CLL patients diagnosed (June 1994-July 2024) at the Shengli Oilfield Central Hospital and Chinese Academy of Medical Sciences & Peking Union Medical College Institute of Hematology. All patients underwent a direct antiglobulin (Coombs) test. Baseline clinical characteristics, first-line treatment regimens, and survival data were collected. Results: The incidence of AIHA among CLL patients was 10.40% (146/1404), with warm AIHA (wAIHA) accounting for 69.18% and cold AIHA (cAIHA) for 30.82%. CLL patients with AIHA were predominantly male, presented with advanced-stage disease, and frequently exhibited splenomegaly, lymphadenopathy involving ≥3 regions, high leukocyte counts, elevated IgM, hypoalbuminemia, elevated β2-microglobulin, and positive immunofixation electrophoresis. Trisomy 12 (CEP12) was more common in CLL patients without AIHA. wAIHA patients were more likely to have high CLL-IPI scores and high leukocyte counts. Molecular profiling revealed a significant association between AIHA and IGHV4-34 gene segment usage (particularly in cAIHA). CLL-AIHA patients in the IGHV4-34 group were predominantly mutated for IGHV (M-IGHV), whereas the non-IGHV4-34 group had higher CLL-IPI scores and was more likely to present with lymphadenopathy and high leukocyte counts. Survival analysis demonstrated significantly shorter time to first treatment (TTFT), progression-free survival (PFS), and overall survival (OS) in AIHA patients compared to non-AIHA patients. Among patients without AIHA, those with unmutated IGHV (UM-IGHV) had shorter TTFT, PFS, and OS than those with mutated IGHV (M-IGHV). However, in CLL patients who develop AIHA, the prognostic value of IGHV mutation status disappears, and there is no significant difference in survival between the wAIHA and cold-type AIHA cAIHA groups. When treatment groups were analyzed separately, AIHA was associated with significantly shorter PFS and OS in patients receiving chemotherapy or immunotherapy, whereas it had no adverse effect on survival among those treated with targeted agents. Conclusion: These findings suggest that AIHA is an adverse prognostic factor in CLL, especially in the era of conventional chemotherapy and chemo-immunotherapy, whereas targeted therapies may offset its negative impact. Therefore, AIHA screening should be intensified in Asian patients with high-risk clinical features or IGHV4-34 positivity, and CLL patients who present with AIHA should be considered for targeted treatment first to improve their survival outcomes.

INTRODUCTION:CD30 is a transmembrane protein of the tumor necrosis factor receptor superfamily. It is expressed on a small subset of activated T and B lymphocytes, and various lymphoid neoplasms, including classical Hodgkin lymphoma and many non-Hodgkin lymphomas in both pediatric and adult populations. AREAS COVERED:This review delves into the significance of CD30 as a therapeutic target and a prognostic indicator for various lymphomas. It provides a comprehensive overview of anti-CD30 therapeutic interventions developed to date, offering insights into the future direction of lymphoma treatment research. Literature search was conducted from January 1987 to December 2024 using PubMed, Scopus, and Web of Science databases to identify relevant studies. EXPERT OPINION:CD30 has emerged as a critical marker of diagnosis, prognosis, and therapeutic strategies of lymphomas. The introduction of brentuximab vedotin (BV) (Adcetris), an antibody-drug conjugate targeting CD30, has significantly advanced the treatment landscape for multiple lymphoma types, demonstrating enhanced efficacy and manageable safety profiles in CD30+ lymphomas patients. However, drug resistance is observed in few patients. Concurrently, innovative therapeutic strategies targeting CD30, such as chimeric antigen receptor T-cells therapies and bispecific antibodies, are in development. This underscores a strong and ongoing research effort aimed at improving the management of patients with CD30+ lymphomas.

ABSTRACT:Monoclonal gammopathy (MG) in chronic lymphocytic leukemia (CLL) portends heterogeneous outcomes, yet its molecular drivers and therapeutic implications remain undefined. In this retrospective analysis of 2075 patients with CLL (1999-2024), MG was detected in 18.47% cases, with immunoglobulin M (IgM) (8.18%), IgG (8.09%), light-chain (1.14%), and IgA (1.06%) subtypes demonstrating divergent clinicogenomic profiles. Patients with IgA-MG were older at diagnosis, whereas those with IgG-MG had a younger age and a higher frequency of mutated immunoglobulin heavy-chain variable (IGHV). In contrast, IgM-MG was associated with unmutated IGHV, elevated lactate dehydrogenase and β2-microglobulin levels, higher frequencies of TP53 aberrations, and enrichment of MYD88, BIRC3, and DDX3X mutations. IgG-MG was associated with shorter time-to-first treatment (TTFT) only, whereas IgM-MG correlated with significantly inferior TTFT, progression-free survival, and overall survival. Subgroup analyses revealed that the adverse prognostic impact of MG was pronounced in IGHV-mutated CLL but attenuated in unmutated cases. Prognostic discrimination by the CLL-International Prognostic Index (CLL-IPI) remained robust regardless of MG status. Notably, patients with IgM-MG did not experience significant survival benefit from targeted therapy compared with conventional regimens. These findings demonstrate that MG subtypes, particularly IgM-MG, define biologically and clinically distinct subsets of CLL. Given the limited efficacy of Bruton tyrosine kinase inhibitors in IgM-MG, immunofixation-based MG profiling may inform risk-adapted treatment strategies and personalized therapy selection.

Background:Although the overall survival of multiple myeloma (MM) has improved significantly, patients with ultra-high-risk features (UHR-MM) had dismal outcomes. New therapies to address this unmet medical need are warranted. Equecabtagene autoleucel (eque-cel) has been approved for patients who have received at least three previous lines of therapy by the Chinese National Medical Products Administration. With good efficacy and safety profile in these patients, eque-cel is being explored in early relapse or newly diagnosed UHR-MM patients, Hereby, we report the primary real world data of eque-cel followed ASCT in UHR-MM patients. Methods:We conducted a retrospective chart review on UHR-MM patients who received eque-cel followed ASCT. UHR-MM are defined as: 1) Genetic ultra-high risk: del(17p)≥60%; or ≥2 high-risk cytogenetic abnormalities including TP53 mutation, del(17p)/P53 deletion, t(4;14), t(14;16), t(14;20), 1q21 gain/ amplification; 2) Primary refractory: Results:From August 2023 to April 2025, 12 UHR-MM patients completed ASCT followed by eque-cel infusion. Six patients received melphalan, five received bendamustine combining melphalan and one patient received fludarabine combining melphalan conditioning. Peripheral stem cell was administrated at (2.3-5.5) × 106 cells/kg, and eque-cel was administrated at 1 × 106 cells/kg for all 12 patients. The median age was 53 years (range: 36-67) and 11 (91.7%) were male. Eight patients (72.7%) had genetic ultra-high risk features, one patients (8.3%) were early progression, and two patients (16.7%) had primary PCL history. Two (16.7%) patients had extramedullary disease. With median 2 (range: 1-4) previous line of therapy, the median disease course is 10.5 months before ASCT. Eleven (91.7%) patients had received daratumumab based triplet or quadruplet therapy. All patients received bridging and 11 received maintenance therapy. Two patients, who had received eque-cel infusion within the preceding 6 months but did not achieve a complete response (CR), subsequently underwent consolidation therapy with eque-cel followed ASCT. With a median follow-up of 196 days (from ASCT date), seven patients (58.3%) experienced grade 1 and three patients (25.0%) experienced grade 2 CRS and fully recovered. Four patients were treated with glucocorticoids. No ICANS event was reported. As expected, AEs are dominated by hematological toxicities. All 12 patients achieved hematopoietic reconstitution within 1 months after ASCT, with a median time of 15 days for ANC reconstitution (≥0.5×109/L) and 11.5 days for PLT reconstitution (≥20×109/L) post ASCT. By July 1st, 2025, the ORR was 100%, with all 12 patients reached CR. All patients are MRD negative. Two patients received first eque-cel 3 month before ASCT, which achieved both VGPR. After ASCT and second eque-cel infusion, achieved sCR and MRD negative status on day 23 and day 190 post-ASCT, respectively. The early progression patient relapsed at 55 days post ASCT, all the other patients are keeping their response and under follow-up. The median DOR, PFS and OS were not reached by cutoff date. Robust CAR T-cell expansion was observed, with a median Tmax of 11 days (range 7~21). The median Cmax was 665.04 cells/μL. The pharmacokinetic profile is similar to that of eque-cel in R/RMM patients. Conclusion:Eque-cel followed ASCT demonstrated promising deep and durable response and was well tolerated in UHR-MM patients. CRS events are slight, hematopoietic reconstruction rate was 100%. We are looking forward to more patients gaining long-term benefit from this new treatment.

Background: Although Bruton tyrosine kinase (BTK) inhibitor monotherapy yields an overall response rate (ORR) of 80–90% and prolongs survival in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), its complete response (CR) rate remains suboptimal (<10%). Even after 7–8 years of continuous treatment, the CR rate only improves to around 30%. More critically, achieving undetectable minimal residual disease (uMRD) is infrequent, compelling patients to undergo long-term BTK inhibitor therapy. To address these limitations, our trial investigated a time-limited combination immunochemotherapy strategy in treatment-naïve CLL patients, aiming to deepen remission, achieve uMRD, and enable treatment cessation to enhance quality of life. Methods: Eligible pts were treatment-naïve CLL/SLL patients aged ≤65 years. The regimen consisted of zanubrutinib (Z) monotherapy (160 mg twice daily) for 12 cycles, followed by four cycles of combination therapy with fludarabine (F, 25 mg/m² IV D1-3 cycles 13-16), cyclophosphamide (C, 250 mg/m² IV D1-3 cycles 13-16), and obinutuzumab (G, 1000 mg IV D0,7,14 cycle 13; 1000 mg IV D0 cycles 14-16) (ZFCG regimen). After cycle 16, response and MRD status in peripheral blood (PB) and bone marrow (BM) were assessed by four-color flow cytometry. Patients achieving CR/CRi with uMRD in both PB and BM could stop treatment; others could choose to continue or stop zanubrutinib monotherapy.（NCT05287984） Results: As of April 1, 2025, 59 pts initiated therapy. Thirty pts completed combination therapy; 3 withdrew (1 due to COVID-19 impact, 2 due to disease progression：one in zanubrutinib monotherapy phase, the other post the ZFCG phase). Baseline characteristics: median age 58 years (range 33-65); 67.8% male. High-risk and very-high-risk CLL-IPI scores were present in 20.3% and 3.4% of pts, respectively. IGHV was unmutated in 38.3%. Cytogenetic abnormalities included TP53 deletion (del) (1.7%), ATM del (15.3%), RB1 del (22.0%), and trisomy 12 (20.3%). TP53 mutation was detected by NGS in 3.4%. All 59 patients received zanubrutinib monotherapy, with 41 progressing to the ZFCG phase. Among the 30 patients who completed 4 cycles of ZFCG and underwent efficacy assessment, after 12 cycles of zanubrutinib monotherapy alone, the CR rate was 13.3% (4/30), and only 1 patient (3.3%) achieved CR with uMRD in both PB and BM. After 2 cycles of ZFCG, 18 patients (60%) achieved both CR and CR with PB+BM uMRD. Upon completion of 4 cycles of ZFCG, the proportion of patients achieving CR and CR with PB+BM uMRD increased to 76.7% (23/30) and 73.3% (22/30), respectively. Additionally, 100% of patients (30/30) achieved PB uMRD, and 96.7% (29/30) achieved BM uMRD. All 30 patients met the criteria for treatment cessation after completing 16 cycles of therapy. With a maximum treatment-free interval of 20 months, 29 patients maintained CR with uMRD without treatment. However, 1 patient experienced disease progression, characterized by the reappearance of a pulmonary mass noted at diagnosis, 7 months post-cessation, although the BM remained in CR with uMRD at recurrence. During the ZFCG phase, the most common grade ≥3 adverse events (AEs) were thrombocytopenia (32.5%), neutropenia (27.5%), and leukopenia (25%). Grade ≥3 non-hematological AEs included lung infection (15%) and febrile neutropenia (5%). Conclusion: The ZFCG regimen demonstrated high rates of CR with uMRD in treatment-naïve CLL patients after 4 cycles of combination therapy, accompanied by excellent uMRD rates in PB and BM. All patients who completed 16 cycles of therapy fulfilled the criteria for treatment cessation. With a median follow-up of nearly 1 year (max 20 months) post-treatment, 29 out of 30 patients maintained continuous CR with uMRD. However, longer follow-up is required to determine the durability of treatment-free remission. These preliminary findings from the Stop Trial indicate that ZFCG is an effective, time-limited treatment option for treatment-naïve CLL patients.

OBJECTIVE:Our previous studies have indicated potentially higher proliferative activity of tumor cells in Chinese patients with mantle-cell lymphoma (MCL) than those in Western. Given the success and tolerability of R-DA-EDOCH immunochemotherapy in treating aggressive B-cell lymphomas, we designed a prospective, phase 3 trial to explore the efficacy and safety of alternating R-DA-EDOCH/R-DHAP induction therapy for young patients with newly diagnosed MCL. The primary endpoint was the complete remission rate (CRR) at the end of induction (EOI). METHODS:A total of 55 patients were enrolled. The CRR at the EOI was 89.1% [95% confidence interval (CI) 78%-96%], and the overall response rate was 98.1% (95% CI 90%-100%). Most patients with bone marrow involvement quickly attained minimal residual disease (MRD) negative status, with a 95.7% rate at the EOI. RESULTS:The 3-year progression-free survival (PFS) and overall survival rates were 66.3% and 83.2%, respectively. No patients discontinued treatment because of adverse events. Univariate analysis identified pathologic morphology and TP53 mutations as risk factors for PFS. However, high tumor proliferative activity and certain cytogenetic abnormalities showed no significant adverse prognostic significance. CONCLUSIONS:Intensive therapy based on a high cytarabine dose and continuously administered EDOCH achieved a high MRD-negative rate and provides an optional induction choice for young patients with MCL with high-risk factors.

PURPOSE:Waldenström macroglobulinemia (WM) is a rare type of lymphoma, with no optimal treatment. Bruton's tyrosine kinase inhibitors have shown promising outcomes, yet achieving deep remission (very good partial remission or complete remission) remains challenging. and time-limited therapy with proteasome inhibition has not been reported. We conducted a phase II clinical trial (NCT04463953) to evaluate the efficacy and safety of combining zanubrutinib, ixazomib, and dexamethasone (ZID) in patients with newly diagnosed WM. PATIENTS AND METHODS:A total of 27 patients were enrolled in the study. Patients received ZID induction therapy for up to six 28-day cycles, followed by consolidation therapy for a total of 24 cycles. The primary endpoint was the deep remission rate. RESULTS:Overall, 24 of the 27 enrolled patients completed induction treatment. One patient (4.2%) achieved complete remission. Ten patients (41.6%) achieved very good partial remission. The overall, major, and deep remission rates were 100%, 95.8%, and 45.8%, respectively. The median time to response was 2 months (range, 1-5). Five of the 22 patients had a CXCR4 mutation, with no disparity in deep remission between the patients with and without a CXCR4 mutation (40% vs. 50%; P = 0.594). The median abnormal lymphocyte (7.6% vs. 1.6%; P = 0.0019) and plasma cells (0.28%-0.02%; P = 0.0306) in bone marrow were significantly reduced after treatment. The median follow-up was 30.9 months (range, 15-42). The estimated median progression-free survival and overall survival were 40 months (95% confidence interval, 35.5-44.5) and not reached, respectively, with no difference in patients with/without CXCR4 mutations. The most common adverse event was hematologic toxicity. CONCLUSIONS:The ZID regimen might offer deep remission and provide a time-limited Bruton's tyrosine kinase inhibitor therapy in patients with WM.

Large granular lymphocytic leukemia (LGLL) is characterized by the clonal proliferation of cytotoxic T lymphocytes or NK cells. Standard first-line immunosuppressive treatments have limitations, achieving complete remission (CR) rates of up to 50%. Immune system dysregulation is implicated in LGLL. Promising results for thalidomide, an immunomodulatory drug, combined with prednisone and methotrexate (TPM), were observed in our pilot study. This multicenter study evaluated the efficacy and safety of a thalidomide, prednisone, and methotrexate (TPM) regimen in 52 symptomatic, methotrexate- and thalidomide-naive LGLL patients from June 2020 to August 2022. Thalidomide (100 mg daily for up to 24 months), prednisone (0.5–1.0 mg/kg every other day, tapered after 3 months), and methotrexate (10 mg/m2 weekly for up to 12 months) were administered. The primary objective was to determine the CR rate. The median follow-up duration was 29.0 months (range: 4.0–42.0). Forty-seven patients (90.4%) achieved hematological and symptomatic responses. Thirty-nine patients (75.0%) achieved CR. The median time to response was 3.0 months (range: 3.0–9.0). The median progression-free survival was 40.0 months (95% confidence interval (CI): 38.0–42.0), and the median duration of response was 39.0 months (95% CI: 36.1–41.9). The most common adverse event was peripheral neuropathy (24.1%), most of which (84.6%) were grades 1–2. Four patients experienced grade ≥3 adverse events. In conclusion, the TPM regimen was an effective and safe treatment for symptomatic LGLL patients, with a particularly high CR rate. This trial was registered at www.clinicaltrials.gov (#NCT04453345).

This study compares the safety profiles of two Bruton's tyrosine kinase (BTK) inhibitors, Ibrutinib and Zanubrutinib, in patients with chronic lymphocytic leukemia (CLL). While Ibrutinib has transformed CLL treatment, it is associated with significant adverse events (AEs). Zanubrutinib, a second-generation BTK inhibitor, offers potential for improved safety. In this prospective study, 200 CLL patients were enrolled, with 100 receiving Ibrutinib and 100 receiving Zanubrutinib. Baseline characteristics such as age, sex, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status, and genetic factors were evaluated. AEs and serious AEs (SAEs) were tracked and graded using the Common Terminology Criteria for Adverse Events (CTCAE). Multivariate logistic regression models were conducted to determine predictors of SAE and AEs grade >= 3. Adjusted odds ratio (aOR) and 95% confidence interval (CI) were reported. The mean ages of the Ibrutinib and Zanubrutinib groups were 49.65 and 49.16 years, respectively (p = 0.285). The Zanubrutinib group had a higher percentage of patients with worse ECOG status (71% vs. 57%, p = 0.039). Fewer Zanubrutinib patients experienced severe AEs (4% vs. 9%, p = 0.152) or SAEs (8% vs. 17%, p = 0.054). Neutropenia occurred only in the Ibrutinib group (3%). Subgroup analysis showed a higher complication rate with Zanubrutinib in non-refractory patients (11.40% vs. 5.26%, p = 0.065). Stage III CLL was a protective factor of grade >= 3 AEs (aOR = 0.007; 95% CI: 0.0003-0.1829) and SAE (aOR = 0.015; 95% CI: 0.001-0.177). While ECOS status (2 vs. 3) resulted in reduced risk of SAE, chromosome 17p deletion emerged as the main risk factor of SAE (aOR = 6.40; 95% CI: 1.33-30.79). Zanubrutinib demonstrated a more favorable safety profile than Ibrutinib, with fewer severe adverse events. It may be a safer alternative for CLL patients, particularly those at higher risk for complications from BTK inhibitors. However, these differences stemmed from variability in baseline clinical characteristics rather than the interventions themselves.

Supplemental Figure 5. Survival outcomes in patients with or without deep remission.

Equecabtagene autoleucel (eque-cel), a fully human BCMA-targeted CAR-T therapy, has exhibited unprecedented efficacy in relapsed/refractory multiple myeloma (RRMM) patients with ≥3 prior lines of therapy (LOT), achieving 96% overall response rates (ORR) in clinical trials. Despite its 2023 approval in China, critical knowledge gaps persist regarding its real-world applicability across heterogeneous patient populations. This is a single-center retrospective study that evaluates the efficacy, safety, and durability of eque-cel in Chinese RRMM patients. The prior lines of treatment (LOT), baseline characteristics before eque-cel infusion, as well as the safety and efficacy of eque-cel were recorded. Categorical variables were analyzed using Fisher's exact test. Survival outcomes including progression-free survival (PFS) and overall survival (OS) were evaluated by Kaplan-Meier methodology and significance testing was conducted using the Log-rank method. We also performed Cox regression analyses for PFS as univariate analyses. From June 2023 to February 2025, totally 45 patients were enrolled, 22 (48.9%) were male, with a median age of 61 years (range, 30-75 years). High-risk cytogenetic abnormalities included G(1q21) in 46.7% (21/45), t(4;14) in 15.6% (7/45), and TP53/del(17p) mutation in 33.3% (15/45). Fifteen patients (33%) harbors at least two high-risk cytogenetic abnormalities. The median number of prior LOT was 2 (range, 1-7), with 46.7% (21/45) having received ≥3 lines. The triple-class exposed rate was 68.9% (31/45), and the autologous stem cell transplantation (ASCT) rate was 37.8% (17/45). All patients received FC lymphodepleting regimen and underwent infusion of 1×10⁶/kg CAR-T cells. The median leukapheresis to infusion interval was 57 days (range, 22-203 days). Individualized bridging therapies were used in 100% of patients. Adverse events were manageable. Cytokine release syndrome (CRS) occurred in 84.4% (38/45) of patients, with grade 3 CRS in 4.4% (2/45) who had received 5 and 7 prior LOT, respectively; immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 6.7% (3/45), comprising two grade 1 events and one grade 3 event. The patient with grade 3 ICANS had received 5 prior LOT. Hematologic toxicities were common, with grade 3-4 neutropenia, anemia, and thrombocytopenia occurring in 60.0% (27/45), 31.1% (14/45), and 24.4% (11/45) of patients, respectively. Non-hematologic toxicities such as nausea (11.1%), diarrhea (20.0%), and headache (4.4%) were less frequent. Infections occurred in 51.1% (23/45) of patients, with grade 3-4 infections in 26.7% (12/45). Before eque-cel infusion, 16 attained complete response (CR), 4 attained VGPR, 12 patients remained with a high M-protein load (≥10 g/L), 2 patients PD, while all the rest were SD. Median follow up 196 days (range, 18-596 days), the overall response rate (ORR) was 95.6%, with 82.2% achieving ≥CR. Furthermore, 93.3% of patients achieved minimal residual disease (MRD) negativity. The median time to response was 28 days (range, 14-85 days). The median time to best response was 60 days (range, 14-231 days). The median PFS and OS were both not reached. For all patients, 1-2 LOT and ≥3 LOT, the 12-month PFS rate were 74.9%, 91.5% and 63.1%, respectively, and the 12-month OS rate were 91.0%, 100% and 82.5%, respectively. Two patients died from infection at 1 month, the other one died at 3 month with unknown reason. Cell kinetic analysis confirmed the presence of CAR-positive T cells in all patients, with median time to peak was 10 days, and the median peak concentration was 423.32 cells/μL. Univariate analysis indicated that 1q21 amplification was significantly negatively correlated with ORR (100% vs 61.9%, p=0.001). Heavily pretreated patients (≥3 lines) and triple-refractory disease showed a trend toward inferior ORR, while patients with t(11;14) translocation showed a trend toward longer PFS (the 12-month PFS rate 100% vs 68.3%, p=0.056). This is the first report on the efficacy and safety of eque-cel in real-world patients with RRMM, which confirmed that eque-cel provided early and deep responses in heavily pretreated RRMM patients, with a manageable safety profile. Preliminary findings from the exploration in early-line RRMM patients also support further investigation in this population.